Casgevy works by sepcifically targeting the BCL11a gene rather than the target DNA sequence itself. This gene is a zinc-finger protein that can bind to specifc DNA sequences. Specifically it is a C2H2 type zinc-finger protein and it plays a heavy roles in diseases such a Sickle Cell Disease and Beta-Thalassemia. BCL11a opperates as deactivator for fetal-hemoglobin, which mitagates the magnitidue of these diseases, so attacking the expression of the gene has been shown to be much more efficicient in taking these disorders down. The problem witht his gene comes down to when it's dysregulated. Because BCL11a encodes a zinc-finger factor which is crucial for monitoring the switch from fetal hemoglobin production to adult hemoglobin production in red blood cells, impacting key functionalities of neurons in the developing brain, and for developing B- and T-lymphocytes, any abnormality in this gene can cause severe damage to a person. Specifically, the overexpression of this gene can cause cancer, hemoglobin pathies, tumors, and diabetes.
BCL11A has other names. It is also understood as ecotropic viral integration site 9 homolog (EVI9) or COUP-TF-interacting protein 1. Chromosome 2p16.1 encodes the gene and mouse Bcl11a (musBcl11a) highly conserves it. BCL11A specifically binds to 5′-GGCCGG-3′ sequences.
The expression of BCL11a is commonly found in enthyroid cells where it serves to repress the y-globin gene expression. Casgevy opperates by targeting the BCl11a erythroid enhancer region. Below some major protein that make up this region are discussed.
The protein Kruppel-like factor 1 (KLF1) is a transcription factor that inhibits γ-globin expression by positively regulating BCL11a. The overexpression of this transcription factor leads to the propagation of sickle cell disease as sickle cell is a β-Hemoglobinopathy.
BCL11A uses an erythroid enhancer for its adult-stage erythroid expression pattern. There are three DNAse 1 hyperactive sites in the BCL11A intron-2. These are called +62, +58, +55 based on distance in kb from the transcription start site (TSS) of BCL11A. The BCL11A erythroid ehancer is on the +58 kb hyperactive site. The proteins GATA1 and TAL1 directly bind to this enhancer. These are major erythroid transciption factors that bind together and with other major proteins, such as LMO2, Lb1, and poteintially Sp1, to regulate HbF expression. TAL1 is required for chromatin loop formation between the LCR and γ-globin gene in human erythroid cells. GATA-1 is also in this area as well, but it's presence in the LCR is not sufficient for the recruitment of these subunits and loop formation. GATA-1 specifically binds to the GATA-1 transcriptional activator binding sequence (GATA motif) in the erythroid specific enhancer region of BCL11A to enhance its expression.